Defense Date

2-21-2014

Graduation Date

Summer 2014

Availability

Immediate Access

Submission Type

dissertation

Degree Name

PhD

Department

Biological Sciences

School

Bayer School of Natural and Environmental Sciences

Committee Chair

Nancy Trun

Committee Member

Jana Patton-Vogt

Committee Member

Joe McCormick

Committee Member

Rita Mihailescu

Keywords

Antibiotic, Cold Shock Protein, DNA binding protein, Drug Discovery, E. Coli, Homology Modeling

Abstract

Escherichia coli K12 has the capacity to express nine Csp (Cold shock-related protein) gene products (CspA-I). These proteins share between 29 and 83 percent identity in their amino acid sequences and only one, CspA, has a solved crystal structure. One of the Csps shown to be involved in chromosome condensation is a 6.3 kDa protein called CspE and deletion studies of its homologues in Bacillus subtilis show that at least one of the Csp proteins is required for cell viability. All of the Csp proteins studied to date bind to single stranded nucleic acids. Knowing that at least one of these proteins is required for cell viability and that the homologues of this protein share high similarities in both structure and function, I have used in silico and in vitro methods to accurately predict structure-function correlations that can be targeted for inhibition by small molecules. Using the structural information of the homologue, CspB, in B. subtilis, co-crystalized with and without its ligand, I have modeled the remaining eight unsolved structures of the Csps in E. coli K12. Using molecular modeling and structures from commercially available databases, I found two lead compounds that could potentially inhibit CspE function. My data suggest that successful small molecule inhibition of CspE could also effect enough of the remaining 8 Csp homologues in E. coli K12 to impact cell viability and provide a means to finding lead compounds for novel antibiotic development.

Format

PDF

Language

English

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